Selective Estrogen Receptor Modulators

ABSTRACT

The present invention relates to a selective estrogen receptor modulator of formula I: I; or a pharmaceutical acid addition salt thereof; useful, e.g., for treating endometriosis and uterine leiomyoma.

FIELD OF INVENTION

The present invention is in the field of medicine, particularly in thetreatment of gynecological disorders. More specifically, the presentinvention relates to selective estrogen receptor modulators useful totreat endometriosis and uterine leiomyoma.

BACKGROUND OF THE INVENTION

Uterine leiomyoma/leiomyomata (uterine fibroid disease) is an old andever present clinical problem that goes under a variety of names,including uterine fibrosis, uterine hypertrophy, uterine leiomyomata,symmetrical hypertrophy, fibrosis uteri, and fibrotic metritis.Essentially, uterine fibrosis is a condition where there is aninappropriate deposition of fibroid tissue on the wall of the uterus.This condition is a cause of dysmenorrhea and infertility in women.

Endometriosis is a condition of severe dysmenorrhea, which isaccompanied by severe pain, bleeding into the endometrial masses orperitoneal cavity and often leads to infertility. The symptom's causeappears to be ectopic endometrial growths that respond inappropriatelyto normal hormonal control and are located in inappropriate tissues.Because of the inappropriate locations for endometrial growth, thetissue seems to initiate local inflammatory-like responses causingmacrophage infiltration and a cascade of events leading to initiation ofthe painful response. Evidence suggests that a cause of uterine fibrosisand endometriosis is an inappropriate response of fibroid tissue and/orendometrial tissue to estrogen.

Many publications have appeared within the last ten years disclosingnovel selective estrogen receptor modulators (SERMs), e.g., U.S. Pat.Nos. 5,484,795, 5,484,798, 5,510,358, 5,998,401 and WO 96/09040. Many ofthese SERMs, generally speaking, have been found to have a beneficialestrogen agonist activity in the bone and cardiovascular systems with aconcomitant beneficial estrogen antagonist activity in the breast. Asmall, particularly useful subset of such compounds has also been foundto have an estrogen antagonist effect in the uterus. A compound withthis particularly useful SERM profile holds particular promise intreating uterine leiomyoma/leiomyomata and/or endometriosis.

However, the actual use of these SERM compounds, particularly inpre-menopausal women, has been hampered due to said compound'sstimulatory effect on the ovaries. A great need currently exists,therefore, for new SERM compounds that behave as estrogen antagonists inthe uterus that do not stimulate the ovaries.

SUMMARY OF INVENTION

The present invention relates to a compound of formula I:

wherein:

m and r are independently 0, 1 or 2;

R is H, SO₂(n-C₄-C₆ alkyl) or COR³;

R⁰ is independently at each occurrence OH, CF₃, halo, C₁-C₆ alkyl orC₁-C₆ alkoxy;

R¹ is C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁴R^(4a), CF₃ or CH₂CF₃;

R² is H or methyl provided that if m is 1 or 2, then R² must be H andthat if m is 0, then R² must be methyl;

R³ is C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁶R^(6a), phenoxy, or phenyloptionally substituted with halo;

R⁴ is C₁-C₆ alkyl or phenyl;

R^(4a), R⁶ and R^(6a) are independently H, C₁-C₆ alkyl or phenyl;

X is O or NR⁷;

Y is O or S; and

R⁷ is H or C₁-C₆ alkyl; or a pharmaceutical acid addition salt thereof.

The present invention also relates to a pharmaceutical composition thatcomprises a compound of formula I, or a pharmaceutical acid additionsalt thereof, and a pharmaceutical carrier. In another embodiment, thepharmaceutical composition of the present invention may be adapted foruse in treating endometriosis and/or uterine leiomyoma.

The present invention also relates to methods for treating endometriosisand/or uterine leiomyoma employing a compound of formula I, or apharmaceutical acid addition salt thereof.

In addition, the present invention relates to a compound of formula I,or a pharmaceutical acid addition salt thereof, for use in treatingendometriosis and/or uterine leiomyoma. The present invention is furtherrelated to the use of a compound of formula I, or a pharmaceutical acidaddition salt thereof, for the manufacture of a medicament for treatingendometriosis and/or uterine leiomyoma.

The present invention further relates to a compound of formula II:

wherein:

m, r, R⁰, R¹, R², R³ and Y are as defined above for a formula I compoundand

s is 0, 1 or 2;

R⁸ is H, C₁-C₆ alkyl, benzyl, SO₂CH₃, SO₂(n-C₄-C₆ alkyl) or COR³;

X¹ is O or NR⁹; and

R⁹ is H, C₁-C₆ alkyl or CO₂(C₁-C₆ alkyl); provided that if s is 2, thenR⁸ is C₁-C₆ alkyl, SO₂CH₃ or benzyl or R⁹ is CO₂(C₁-C₆ alkyl); or anacid addition salt thereof; useful as an intermediate to a compound offormula I.

DETAILED DESCRIPTION

Unless specified otherwise, reference hereafter to a “compound offormula I” includes the pharmaceutical acid addition salts thereof.

The compounds of the present invention have one or more chiral centersand may exist in a variety of stereoisomeric configurations. As aconsequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

For the purposes of the present invention, as disclosed and claimedherein, the following terms are defined below.

The term “halo” refers to fluoro, chloro, bromo and iodo. The term“C₁-C₆ alkyl” represents a straight, branched or cyclic hydrocarbonmoiety having from one to six carbon atoms, e.g., methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and the like.Moieties such as a cyclobutylmethylene are also included within thescope of a C₁-C₆ alkyl group. The term “C₁-C₄ alkyl” refers specificallyto methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl,n-butyl, isobutyl, sec-butyl, t-butyl and cyclobutyl. The term “n-C₄-C₆alkyl” refers specifically to n-butyl, n-pentyl and n-hexyl. A “C₁-C₆alkoxy” group is a C₁-C₆ alkyl moiety connected through an oxy linkage.

The term “pharmaceutical” when used herein as an adjective meanssubstantially non-deleterious.

A pharmaceutical “acid addition salt” is a salt formed by reaction ofthe free base form of a compound of formula I with a pharmaceuticalacid, such as described in the Encyclopedia of PharmaceuticalTechnology, editors James Swarbrick and James C. Boylan, Vol 13, 1996“Preservation of Pharmaceutical Products to Salt Forms of Drugs andAbsorption”. Specific salt forms include, but are not limited to the:acetate, benzoate, benzenesulfonate, 4-chlorobenzenesulfonate; citrate;ethanesulfonate; fumarate; d-gluconate; d-glucuronate; glutarate;glycolate; hippurate; hydrochloride; 2-hydroxyethanesulfonate;dl-lactate; maleate; d-malate; 1-malate; malonate; d-mandelate;1-mandelate; methanesulfonate; 1,5 napthalenedisulfonate;2-naphthalenesulfonate; phosphate; salicylate; succinate; sulfate;d-tartrate; 1-tartrate; and p-toluenesulfonate.

The term “patient” as used herein refers to female humans and non-humanfemale animals such as companion animals (dogs, cats, horses and thelike).

The terms “treating” and “treat” as used herein, means alleviating,ameliorating, preventing, prohibiting, restraining, slowing, stopping,or reversing the progression or severity of a pathological condition, orsequela thereof, described herein. The term “preventing” means reducingthe likelihood that the recipient of a compound of formula I will incur,further incur or develop any of the pathological conditions, or sequelathereof, described herein.

The term “patient in need thereof” is a patient either suffering fromthe claimed pathological condition or sequela thereof, or is a patientat a recognized risk thereof, as determined by medical diagnosis, i.e.,as determined by the attending physician.

As used herein, the term “effective amount” means an amount of acompound of formula I that is capable of treating the conditionsdescribed herein.

Preferred Compounds and Embodiments of the Invention

Certain compounds of the invention are particularly interesting and arepreferred. The following listing sets out several groups of preferredcompounds. It will be understood that each of the listings may becombined with other listings to create additional groups of preferredcompounds. The following numbering system will be used to describe thepreferred positions of the SO₂R¹ moiety:

a) m is 1 or 2;

b) m is 1;

c) r is 0;

d) r is 1 and R⁰ is OH, CF₃, fluoro, C₁-C₄ alkyl or C₁-C₄ alkoxy;

e) r is 1 and R⁰ is fluoro;

f) R is H;

g) R is H or COR³ and R³ is C₁-C₆ alkyl, NHCH₃ or phenyl;

h) R is H or COR³ and R³ is C₁-C₄ alkyl, NHCH₃ or phenyl;

i) the —SO₂R¹ moiety is at the 4-position;

j) the —SO₂R¹ moiety is at the 5-position and R¹ is NR⁴R^(4a) or CF₃ andR⁴ is C₁-C₄ alkyl and R^(4a) is H or C₁-C₄ alkyl;

k) R¹ is C₁-C₄ alkyl, NR⁴R^(4a) or CF₃ and R⁴ is C₁-C₄ alkyl and R^(4a)is H or C₁-C₄ alkyl;

l) R¹ is methyl, ethyl, cyclopropyl, NHCH₃, N(CH₃)₂ or CF₃;

m) R¹ is methyl or N(CH₃)₂;

n) R¹ is methyl;

o) R¹ is N(CH₃)₂;

p) X is O;

q) X is NR⁷ and R⁷ is H or methyl;

r) Y is O;

s) the hydrochloride salt form.

With respect to the chiral center designated below:

an enantiomeric excess (ee) of greater than 90% is preferred, an ee ofgreater than 95% is most preferred and an ee of greater than 99% is mostespecially preferred. Enantiomeric enrichment is readily determined byone of ordinary skill in the art using standard techniques andprocedures, such as gas or high performance liquid chromatography with achiral column (see, e.g., J. Jacques, et al., “Enantiomers, Racemates,and Resolutions”, John Wiley and Sons, Inc., 1981; E. L. Eliel and S. H.Wilen,” Stereochemistry of Organic Compounds”, (Wiley-Interscience1994), and European Patent Application No. EP-A-838448, published Apr.29, 1998). Of course, the preferred enantiomer is that which possessesfavorable activity in the biological assays disclosed herein. Employingthe chiral chromatography disclosed in the Examples below, the preferredenantiomer (the enantiomer with favorable activity) typically possessesthe slower retention time, i.e., elutes second. In order to verify theidentify of the preferred enantiomer in any given racemic mixture, theactivity of the individual isomers should be verified in the biologicalassays described herein.

The preferred patient of treatment is a female human.

The compound of formula I is preferably formulated in a dosage unitform, i.e., in an individual delivery vehicle, for example, a tablet orcapsule, prior to administration to the recipient woman.

The compound of formula I is preferably administered orally.

Synthesis

The compound of formula I may be prepared as described in the followingExamples and as described in Scheme 1 where R¹⁰ is fluoro or an alkylprotected hydroxy or thio moiety.

In Scheme 1, a compound of formula IV is reacted with a compound offormula III under usual “Suzuki” or “Stille” reaction conditions, i.e.,wherein one of substituent “A” or “D” is a boronic acid/ester or alkylstannane moiety and the other is a leaving group, e.g., chloro, bromo oriodo or a sulfonate group such as trifluoromethyl sulfonate to provide acompound of formula V.

When R¹⁰ is protected hydroxy, said hydroxy group is typically removedin order to promote the following reduction/cyclization reaction. Saidprotecting group may be removed via standard procedure, e.g., thosedescribed in the Examples below or as taught in the latest edition ofGreene, Protective Groups in Organic Synthesis, John Wiley & Sons, NewYork, N.Y.). After removal of the hydroxy protecting group, the ketogroup found in the resulting product compound of formula V may then bereduced under standard conditions, e.g., employing borane to provide thecorresponding compound of formula III where Z is CHOH. This reducedproduct may then be cyclized under standard conditions, e.g., when R¹⁰is F, base catalyzation with potassium t-butoxide or when R¹⁰ is otherthan F, acid catalyzation with HCl, to provide the correspondingcompound of formula I or II.

When s is 0 or 1, the cyclized product may be oxidized under standardconditions (see working examples below) to prepare the correspondingsulfone of formula I. When R⁸ is SO₂CH₃, C₁-C₆ alkyl or benzyl(preferably methyl, benzyl or SO₂CH₃) said hydroxy protecting groups maybe removed under standard conditions (see, e.g., the procedures thatfollow or the latest edition of Greene, Protective Groups in OrganicSynthesis, John Wiley & Sons, New York, N.Y.) to provide the compound offormula I where R is H. Similarly, when X¹ is NR⁹ and R⁹ is CO₂(C₁-C₆alkyl), said amino protecting group may also be removed as taught inGreene. A formula I compound where R is H may be further derivatizedemploying standard acylation or sulfonylation methodology to prepare acompound of formula I where R is COR³ or SO₂(n-C₄-C₆ alkyl).

A compound of formula I may also be prepared by introducing an SR¹moiety post-cyclization by nucleophilic displacement of fluorinefollowed by oxidation to the corresponding sulfone as described inExamples 8 and 9 below.

Compounds of formula III may be prepared as shown below or by proceduresanalogous to those found in the art. Compounds of formula IV are, ingeneral, commercially available or can be prepared by procedures readilyavailable to the ordinarily skilled synthetic organic chemist or asshown below.

GENERAL EXPERIMENTAL DETAILS

Electrospray mass spectra may be obtained on a Finnigan LCQ Duoinstrument using a mobile phase of 50% acetonitrile, 25% methanol, and25% 2mM aqueous ammonium acetate. Preparative HPLC's may be obtained ona Gilson Preparative System with Unipoint Software and dual wavelengthdetection at 220 and 254 nm as well as Finnigan aQa MS. A 20-mm×250 -mmODS-AQ column with a particle size of 15 microns may be used as thestationary phase. The eluent is a binary system of bottle A (0.1%trifluoroacetic acid (TFA), 1% isopropyl alcohol (IPA) in water) andbottle B (0.05% TFA, 1% IPA in acetonitrile). The standard method is agradient of 30-95% B unless otherwise indicated. The compounds purifiedby this method are isolated as TFA salts.

Preparative HPLC's may also be obtained on a Biotage ParallelFlex systemwith proprietary dual wavelength detection and software. A 30-mm×150-mmor 19-mm×250 mm Xterra column with a particle size of 10 microns is usedas the stationary phase and 10 mM NH₄ ⁺HCOO⁻/10 mM NH₄OH is used asmobile phase A and 100% acetonitrile is used as a mobile phase B.

Preparation 1 1-Bromo-2-isopropoxy-4-methylthio-benzene

Add 2-Bromopropane (6.0 mL, 0.062 mol, Aldrich) and potassium carbonate(21.0 g, 0.156 mol) to a solution of 2-bromo-5-fluorophenol (10.0 g,0.052 mol) in 80 mL of acetone. Heat the mixture in a 70° C. oil bath,and stir under reflux for 17 hours. Remove the solvents in vacuo, add200 mL water, and extract the mixture 3 times with dichloromethane. Drythe combined organic layers over Na₂SO₄, and evaporate the solvents invacuo.

Dissolve the residue (5.0 g, 21.45 mmol) in 25 mL of dimethylformamide(DMF) at room temperature. Add NaSCH₃ (1.87 g, 26.81 mmol) all at once.Fit the reaction vessel with a reflux condenser then heat to 60° C. withstirring for 2 hours. Cool the reaction to room temperature, then add 50mL of H₂O, and extract the mixture 3 times with dichloromethane. Combinethe organics, dry over Na₂SO₄ and remove the solvents in vacuo. Purifythe residue by column chromatography on a 90 g SiO₂ cartridge, using 5%ethyl acetate (EtOAc)/hexanes at first, then 20% EtOAc/hexanes to give3.99 g, (15.2 mmol, 71.2% yield) of the title compound.

Preparation 2 Trifluoromethanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester

Dissolve 2,6-dimethoxynaphthalene (1.0 equivalent (eq)) in CH₂Cl₂ (5volume equivalents) at ambient temperature in a dry round bottom flaskequipped with stir bar, temperature probe and N₂ line. Cool the solutionto 0° C. with an ice bath, and add 4-(2-piperidin-1-yl-ethoxy)-benzoylchloride (1.1 eq). Add aluminum chloride (2.0 eq). Once the reaction isdetermined to be complete, quench the reaction slowly with 1 N NaOH anddilute with additional water and CH₂Cl₂. Wash the aqueous layer withCH₂Cl₂ (20 mL). Combine the organic extracts and wash with brine and dry(Na₂SO₄). Recrystallize the crude product from methanol to give(2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone.

Dissolve(2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanonein CH₂Cl₂ (10 volume equivalents) in a 3-neck round bottom flaskequipped with a pressure equalizing addition funnel, stir bar, and N₂source. Cool the flask in an ice/brine bath and add 1.0 M BCl₃ solutionin CH₂Cl₂ (1.2 eq) dropwise. After about 1 hour, quench the reactionwith methanol (5 eq) and allow the reaction to warm to room temperature.Dilute the organic solution with CH₂Cl₂ (one volume eq) and add a 1.0 MNaHCO₃ solution (5 volume eq) and stir for one hour. Separate theaqueous and organic layers. Wash the aqueous layer with CH₂Cl₂ (onevolume) and combine the organic layers. Wash with saturated NH₄Cl anddry over Na₂SO₄. Purify the product via column chromatography (50/1silica gel) eluting with CH₂Cl₂/hexanes (3/1) to yield(2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone.

Dissolve(2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanonein CH₂Cl₂ (10 volumes) in a three neck round bottom flask equipped witha stir bar and N₂ source and chill to 0° C. in an ice/brine bath. Addpyridine (1.3 equivalents) and trifluoromethanesulfonyl chloride (1.2equivalents) via syringe over 15 minutes. After about 15 minutes, quenchthe reaction with H₂O (10 volumes), wash with 1 N aqueous HCl (5volumes) and 1.0 N aqueous NaHCO₃, and dry over Na₂SO₄. Obtain the titlecompound in quantitative yield after concentration.

Preparation 3[2-(2-Isopropoxy-4-methanesulfanyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Dissolve trifluoro-methanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester(1.9 g, 3.18 mmol) in 30 mL acetonitrile, and degas 3 times. Addbis-neopentylglycolato diborane (789 mg, 3.51 mmol), palladium acetate(107 mg, 0.48 mmol) and tricyclohexyl phosphine (200 mg, 0.717 mmol) allat once, and again degas the mixture. Stir for 5 minutes to completelydissolve the reagents. Add cesium fluoride (4.3 g, 28.6 mmol) all atonce, and immediately plunge the reaction vessel into a 90° C. preheatedoil bath. After 2-3 minutes, add1-bromo-2-isopropoxy-4-methanesulfanyl-benzene (0.915 g, 3.51 mmol) in 5mL acetonitrile. After stirring at 90° C. for 20 minutes, cool thereaction, filter through a 2 g SiO₂ plug, and remove the solvents invacuo. Dilute the residue with dichloromethane (DCM)/isopropanol(i-PrOH) (4:1) (100 mL), wash once with 100 mL H₂O, once with 100 mLbrine, dry over Na₂SO₄, and remove the solvents in vacuo. Isolate thetitle compound via silica gel chromatography using 20% tetrahydrofuran(THF)/hexanes with 1% (2N NH₃/methanol (MeOH)) initially, then 20%THF/hexanes with 2% (2N NH₃/MeOH) to elute the compound to give 960 mg(52.8% yield). MS: 570 (M+1).

EXAMPLE 18-Methylsulfanyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl-5H-6-oxa-chrysen-2-olhydrochloride

Dissolve[2-(2-isopropoxy-4-methanesulfanyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(960 mg, 1.68 mmol) in dichloromethane. Bubble HCl (g) through thesolution for 5 minutes. Remove solvents in vacuo, dissolve the residuein dichloromethane (20 mL), cool to −10° C., and add 0.637 mL (6.74mmol) of BBr₃ dropwise. Stir the reaction for 0.5 hours at −10° C., thenpour into a solution of 100 mL of cold aqueous NaHCO₃. Extract themixture 3 times with 20 mL of dichloromethane (DCM), 3 times with 20 mLDCM/i-PrOH (4:1), and then remove the solvents in vacuo.

Dissolve the residue in THF, place under N₂, and add lithium aluminumhydride (1.0 M, 6.74 mL, 6.74 mmol) dropwise, slowly. Stir for one hourat room temperature. Add H₂O slowly to quench. Add 30 mL 1.0N HCl, andstir at room temperature for 1 hour. Isolate via silica gelchromatography (20% THF/hexanes with 0% to 10% (2N NH₃/MeOH)). Isolatethe title compound to give 355 mg, 0.71 mmol, 42.4% yield.

Preparation 4 1-Bromo-2-isopropoxy-4-methanesulfonyl-benzene

Dissolve the compound of preparation 1 (3.99 g, 15.28 mmol) in aceticacid (HOAc) at room temperature, under N₂. Add NaBO₃.H₂O (3.35 g, 33.61mmol) all at once, and stir the reaction at room temperature for 17hours. Remove the solvent in vacuo and add H₂O (30 mL). Extract themixture 3 times with dichloromethane, combine the organics, dry overNa₂SO₄, and remove the solvents in vacuo to give the title product (4.06g, 12.21 mmol, 79.9% yield.

Preparation 5[2-(2-Isopropoxy-4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Dissolve trifluoromethanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester(6.0 g, 11.16 mmol) in 100 mL acetonitrile, and degas 3 times. Addbis-neopentylglycolato diborane (2.76 g, 12.3 mmol), palladium acetate(375 mg, 1.7 mmol) and tricyclohexyl phosphine (703 mg, 2.5 mmol) all atonce, and again, degas the mixture. Stir for 5 minutes to completelydissolve the reagents. Add cesium fluoride (15.17 g, 100 mmol), all atonce, and immediately plunge the reaction vessel into a 90° C. preheatedoil bath. After 2-3 minutes, add1-bromo-2-isopropoxy-4-methanesulfonyl-benzene (3.6 g, 12.3 mmol)dissolved in 20 mL acetonitrile. After stirring at 90° C. for 20minutes, cool the reaction, filter through a 2 g SiO₂ plug, and removethe solvents in vacuo. Dilute the residue with DCM/i-PrOH (4:1) (500mL), wash once with 100 mL H₂O, once with 100 mL brine, dry over Na₂SO₄,and remove the solvents in vacuo to give the title compound (7.1 g, 99%yield). MS: 602 (M+1).

Preparation 6[6-Hydroxy-2-(2-hydroxy-4-methanesulfonyl-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Dissolve[2-(2-isopropoxy-4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(7.1 g, 11.16 mmol) in acetonitrile, and add 2.79 mL of 5N HCl. Stir thereaction for 30 minutes at room temperature and remove the solvents invacuo. Dissolve the residue in dichloromethane (1L), cool to −10° C.,and add 5.28 mL (55.8 mmol) of BBr₃ dropwise. Stir the reaction for 2hours at −10° C., at which time add another 3.17 mL (33.48 mmol) ofBBr₃. Stir for an additional 3 hours, then pour into a solution of 500mL of cold aqueous NaHCO₃. Extract the mixture 3 times with 100 mL ofDCM, 3 times with 100 mL DCM/i-PrOH (4:1), and then filter the aqueouslayer through a glass frit. Dry the filtrate under vacuum for 17 hoursto give the title product (3.18 g, 5.83 mmol, 52.2% yield). MS: 546(M+1).

EXAMPLE 28-Methanesulfonyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol

Stir[6-hydroxy-2-(2-hydroxy-4-methanesulfonyl-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(3.18 g, 5.83 mmol) to dissolve in THF at room temperature, under N₂.Add lithium aluminum hydride (1.0 M, 17.5 mL, 17.4 mmol) dropwise,slowly and stir the reaction at room temperature for 2 hours. Carefullyadd HCl (1.0 N, 29.14 mL, 29.1 mmol) to the reaction mixture. After theaddition is complete, add 2.0 mL of 5N HCl and stir the reaction at roomtemperature for 2 hours. Heat the mixture to 50° C. on a water bath, andstir for 20 minutes. Evaporate the THF in vacuo, and add saturatedaqueous NaHCO₃ solution until the mixture is neutral. Extract 3 timeswith 100 mL DCM/i-PrOH (4:1). Combine the organic layers over Na₂SO₄,and remove the solvents in vacuo.

Purify through a 120 g SiO₂ cartridge using 20% THF/Hexanes with 5% (2NNH₃/MeOH) with a manual gradient to 40% THF/Hexanes with 12% (2N ammoniain methanol NH₃/MeOH) to isolate the title compound (3.8 g, 2.2 mmol,38.8% yield). LCMS: 531 (M+1), 529 (M−1).

EXAMPLE 38-Methanesulfonyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol,mono-Hydrochloride salt

Stir to dissolve8-methanesulfonyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-olin dichloromethane, bubble HCl gas through for 3 minutes, and stir thesolution for 10 minutes. Add ethyl acetate and remove the solvents invacuo to give the title compound. LCMS: 100%, 530 (M+1), 528 (M−1).Separate the racemic mixture into its constituent enantiomers by chiralchromatography (Examples 3a and 3b).

Preparation 7 1-Bromo-2-isopropoxy-4-fluoro-benzene

Add 2-bromopropane (3.14 mL, 33 mmol) and potassium carbonate (9.20 g,67 mmol) to a solution of 2-bromo-5-fluorophenol (5.80 g, 30 mmol) inanhydrous acetone (60 mL). Heat the mixture at reflux for 24 hours.Filter the reaction mixture and concentrate the filtrate in vacuo.Purify by silica gel chromatography, eluting with hexane, to give thetitle product (6.56 g, 92% yield).

Preparation 8 1-Bromo-2-isopropoxy-4-benzylthiobenzene

Cool a suspension of sodium hydride (1.63 g, 68 mmol) in dryN,N-dimethyl formamide (25 mL) in an ice water bath, and then add benzylmercaptan (4.44 g, 34 mmol) slowly. After 30 minutes add an additional 5mL of N,N-dimethyl formamide followed by1-bromo-2-isopropoxy-4-fluoro-benzene (7.93 g, 34 mmol). Warm thereaction mixture to room temperature and stir for 24 hours. Dilute themixture with DCM (100 mL), wash with H₂O, NaHCO₃, dried over Na₂SO₄, andevaporate the solvent in vacuo. Purify by silica gel chromatographyeluting with hexane to yield the title product (0.994 g, 9% yield).

Preparation 9 1-Bromo-2-isopropoxy-4-N,N-dimethyl sulfonamide

Cool a solution of 1-bromo-2-isopropoxy-benzylthiobenzene (990 mg, 3.07mmol) in a mixture of dichloromethane/acetic acid/water (12.5%/5%/2.5%,30 mL, 0.1M) and maintain at 5° C. Slowly bubble gaseous chlorine intothe solution for 3 hours. Dilute the solution with DCM (400 mL) and washtwice with H₂O, once with saturated aqueous NaHCO₃, and again with H₂O.Dry the DCM phase over Na₂SO₄ and concentrate in vacuo to afford the1-bromo-2-isopropoxy-4-sulfonylchloride intermediate. Dissolve thisintermediate (0.96 g, 3.0 mmol) in THF with 2M dimethylamine in THF (7.5ml, 15 mmol) and heat at 60° C. under a N₂ atmosphere for 30 minutes.Dilute the solution with ether, wash twice with 0.1 N HCl, saturatedaqueous NaHCO₃ and H₂O. Dry the ether phase over Na₂SO₄ and concentratein vacuo. Purify by silica gel chromatography eluting with CH₂Cl₂ togive the title compound (560 mg, 1.74 mmol, 57% yield).

Preparation 10 [2-(2-isopropoxy-4-,N,N-dimethylsulfonamide-phenyl)-6-methoxy-1-napthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Dissolve 2-trifluoromethanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-napthalen-2-yl ester(0.61 g, 1.13 mmol) in 15 mL acetonitrile and degas under N₂. Addbis-neopentylglycolato diborane (0.28 g, 1.24 mmol), palladium acetate(0.04 g, 0.186 mmol), and tricyclohexyl phosphine (0.087 g, 0.28 mmol),and degas again under N₂. Stir the mixture until all reagents dissolve.Add cesium fluoride (1.71 g, 11.3 mmol), and immediately place thereaction into a 90° C. preheated oil bath. After 3-7 minutes, add1-bromo-2-isopropoxy-4-N,N-dimethyl sulfonamide ( 0.4 g, 1.24 mmol) in10 mL acetonitrile and the stir the mixture at 90° C. for 6 hours. Coolthe mixture, filter through a thin layer silica gel and wash the silicawith acetonitrile. Concentrate the filtrate in vacuo and purify bysilica gel chromatography (20% THF/Hexane with gradient 0 to 5% 2NNH₃/MeOH) to yield the title compound (363 mg, 51% yield). MS: 631(M+1).

Preparation 11 [2-(2-hydroxy-4-,N,N-dimethylsulfonamide-phenyl)-6-hydroxy-1-napthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Slowly bubble gaseous HCl into a solution of[2-(2-isopropoxy-4-,N,N-dimethylsulfonamide-phenyl)-6-methoxy-1-napthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(0.363 g, 0.58 mmol) in DCM (10 mL). Stir the solution for 15 minutes,and concentrate in vacuo. Dissolve the residue in DCM (10 mL), cool to0° C., and add boron tribromide (0.22 ml, 2.3 mmol) dropwise. Stir thereaction at 0° C. for 2 hours, and then stir at room temperature for 1hour. Add saturated aqueous NaHCO₃ (100 mL), extract the aqueous mixture3 times with DCM/i-PrOH (4:1), dry over Na₂SO₄, and concentrate in vacuoto give the title product (650 mg). MS: 575 (M+1).

EXAMPLE 4 8-N,N-dimethylsulfonamide-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxachrysen-2-oltrifluoroacetate salt

Dissolve [2-(2-hydroxy-4-,N,N-dimethylsulfonamide-phenyl)-6-hydroxy-1-napthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(650 mg, 1.13 mmol) in THF (15 mL) at room temperature, under N₂. Slowlyadd lithium aluminum hydride dropwise and stir the reaction at roomtemperature for 24 hours. Quench the mixture with H₂O (a few drops)until no further gas evolution, and then add HCl (5N, 6 mL). After agingthe mixture at room temperature for four hours, remove the THF in vacuo,and add saturated aqueous NaHCO₃ until the mixture is neutral to hydrionpaper. Extract the aqueous phase 3 times with DCM/i-PrOH (4:1) and drythe combined organic layers over Na₂SO₄. Evaporation of solvent yields acrude solid which is purified by silica gel chromatography eluting with5% 2N NH₃/MeOH in CH₂Cl₂ to give the title product (140 mg, 0.25 mmol,22% yield). MS:559.2 (M+1).

Preparation 12 1-bromo-2-isopropoxy-4-N-methyl sulfonamide

Dissolve 1-bromo-2-isopropoxy-4-sulfonylchloride (0.73 g, 2.3 mmol) in2M methylamine in THF (17.25 mL, 34.5 mmol) and heat at 60° C. under aN₂ atmosphere for 30 minutes. Dilute the solution with DCM, wash twicewith 0.1 N HCl, saturated aqueous NaHCO₃, and H₂O. Dry the ether phaseover Na₂SO₄ and concentrate in vacuo. Purify by silica gelchromatography eluting with CH₂Cl₂ to yield the title compound (390 mg,1.27 mmol, 54% yield). MS: 307 (M−1).

Preparation 13 [2-(2-isopropoxy-4-N-methylsulfonamide-phenyl)-6-methoxy-1-napthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Dissolve 2-trifluoromethanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-napthalen-2-yl ester(590 mg, 1.10 mmol) in 15 mL of acetonitrile, and degas under N₂. Addbis-neopentylglycolato diborane (270 mg, 1.21 mmol), palladium acetate(0.038 g, 0.16 mmol), and tricyclohexyl phosphine (69 mg, 0.25 mmol)and, again, degas under N₂. Stir the mixture until the reagents arecompletely dissolved. Add cesium fluoride (1.5 g, 9.9 mmol) and placethe reaction immediately into a 90° C. preheated oil bath. After 3-7minutes, add 1-bromo-2-isopropoxy-4-N-methyl sulfonamide (370 mg, 1.21mmol) in 10 mL acetonitrile. After stirring at 90° C. for 24 hours, coolthe reaction, filter through a thin layer of silica gel withacetonitrile and concentrate the filtrate in vacuo. Purify the darksolid by silica gel chromatography eluting with 20% THF/hexanes withgradient from 5 to 10% 2N NH₃/MeOH to yield the title product (268 mg,40% yield). MS: 617.26 (M+1).

Preparation 14 [2-(2-hydroxy-4-N-methylsulfonamide-phenyl)-6-hydroxy-1-napthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

Slowly bubble gaseous HCl into a solution of[2-(2-isopropoxy-4-,N-methylsulfonamide-phenyl)-6-methoxy-1-napthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(0.267 g, 0.43 mmol) in DCM (10 mL). Stir the solution for 15 minutesand concentrate in vacuo. Dissolve the residue in DCM (10 mL), cool to0° C. and add boron tribromide (0.164 ml, 1.73 mmol) dropwise. Stir thereaction at 0° C. for 2 hours and then stir at room temperature for 1hour. Add saturated aqueous NaHCO₃ (100 mL), extract the aqueous mixture3 times with CH₂Cl₂/i-PrOH (4:1), dry over Na₂SO₄, and evaporate invacuo to give the title compound (160 mg, 67% yield).

EXAMPLE 5 8-N-methylsulfonamide-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxacbrysen-2-ol

Dissolve [2-(2-hydroxy-4-,N-methylsulfonamide-phenyl)-6-hydroxy-1-napthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(160 mg, 0.29 mmol) in room temperature THF (10 mL), under N₂. Slowlyadd lithium aluminum (1.43 mL, 1.43 mmol) hydride dropwise and stir themixture at room temperature for 24 hours. Quench the mixture with H₂O(few drops) until no further gas evolution and add HCl (5N, 1.4 mL).Stir the reaction at 50° C. in a water bath for one hour. Remove the THFin vacuo and add saturated aqueous NaHCO₃ until the mixture is neutralto hydrion paper. Extract the aqueous phase 3 times with DCM/i-PrOH(4:1) and dry the combined organic phase over Na₂SO₄. Evaporate thesolvent and purify by silica gel chromatography using a gradient of 0 to5% 2N NH₃/MeOH in CH₂Cl₂ to give the title compound (95 mg, 60% yield).MS: 545 (M+1).

Preparation 151-{2-[4-(8-fluoro-2-methoxy-5H-6-oxa-chrysen-5-yl)-phenoxy]-ethyl}-piperidine

Dissolve trifluoromethanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester(1.0 g, 1.86 mmol) in 25 mL acetonitrile and degas 3 times. Addbis-neopentylglycolato diborane (525 mg, 2.33 mmol), palladiumn acetate(63 mg, 0.28 mmol) and tricyclohexyl phosphine (117 mg, 0.42 mmol) allat once, and, again, degas the mixture. Stir for 5 minutes to completelydissolve the reagents. Add cesium fluoride (2.54 g, 16.7 mmol), all atonce, and immediately plunge the reaction vessel into a 90° C. preheatedoil bath. After 2-3 minutes, add 1-bromo-2-benzyloxy-4-fluorobenzene(654 mg, 2.33 mmol) in 5 mL acetonitrile. After stirring at 90° C. for18 hours, cool the reaction, filter through a 2 g silica gel plug, andremove the solvents in vacuo. Dilute the residue with DCM/isopropanol(4:1) (40 mL), wash once with H₂O, once with brine and dry the organiclayer over Na₂SO₄. After evaporation of solvent, isolate[2-(2-benzyloxy-4-fluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanonevia silica gel chromatography using DCM with 2% (2N NH₃/MeOH) to give495 mg, 45% yield. Electrospray MS: 590 (M+1).

Dissolve[2-(2-benzyloxy-4-fluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(470 mg, 0.80 mmol) in 20 ml dry THF under a nitrogen atmosphere. Addlithium aluminum hydride (1.0 M in THF, 1.2 mL, 1.2 mmol) dropwise,slowly. Stir for 1.5 hours at room temperature. To quench the reaction,add 0.5 ml H₂O dropwise, followed by 0.5 ml 1 N NaOH solution, then 1.5ml H₂O. The mixture is then partitioned between ethyl acetate and water.Extract the aqueous layer two more times with 25 mL ethyl acetate, washthe combined organic layers with brine and dry over anhydrous sodiumsulfate. Evaporation of the solvent yields[2-(2-Benzyloxy-4-fluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanol,0.47 g, 99% yield. Electrospray MS: 592 (M+1).

Dissolve[2-(2-Benzyloxy-4-fluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanol(265 mg, 0.45 mmol) in 25 ml absolute ethanol under a nitrogenatmosphere. Add 60 mg of 10% palladium on carbon, wet (Degussa type E101NE/W) and stir at room temperature under a blanket of hydrogen for sixhours. Filter the mixture through a diatomaceous earth pad and evaporatethe filtrate to give a crude foam residue.

Dissolve this residue in 8 ml of THF and 2.5 ml of 1 N aqueous HCl andstir at room temperature for 24 hours. Neutralize the mixture withsaturated aqueous Na₂CO₃ and partition between ethyl acetate and water.Extract the aqueous layer twice more with 25 ml ethyl acetate and washthe combined organic layers with brine and dry over anhydrous sodiumsulfate. The residue obtained after evaporation of the solvent ispurified by radial chromatography (silica, CH₂Cl₂, gradient from 2% to5% 2M NH₃ in methanol) to yield the title compound, 110 mg, 53%.Electrospray MS: 484 (M+1).

EXAMPLE 68-Ethanesulfanyl-5-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol

Dissolve1-{2-[4-(8-fluoro-2-methoxy-5H-6-oxa-chrysen-5-yl)-phenoxy]-ethyl}-piperidine(172 mg, 0.356 mmol) in 5 ml dry dimethylformamide with sodiumethanethiolate (300 mg, 3.56 mmol) under a nitrogen atmosphere and heatto 90° C. for 17 hours. Reduce the volume by 75% by distillation ofsolvent and partition the remaining residue between water and 15%isopropanol in chloroform. Wash the aqueous layer twice more with 15%isopropanol in chloroform, wash the combined organic layers with brineand dry over anhydrous sodium sulfate. Purify the residue obtained afterevaporation of solvent by radial chromatography (silica, DCM/2M ammoniain methanol, gradient from 98:2 to 94:6 to give 164 mg (88%) of thetitle product. Electrospray M. S. m+1=512.

EXAMPLE 78-Ethanesulfonyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-olhydrochloride salt

Dissolve8-ethanesulfanyl-5-[4-(3-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol(160 mg, 0.313 mmol) in 4 ml glacial acetic acid, add sodium perborate(66 mg, 0.657 mmol) and stir at room temperature for 16 hours. Evaporatethe solvent and purify the residue by radial chromatography (silica,DCM/2M ammonia in methanol, gradient from 98:2 to 95:5). Dissolve thepurified residue obtained after evaporation of solvent in DCM and asmall amount of HCl gas bubbled into the solution. Dilute the mixturewith ethyl acetate and evaporate the solvent to give the title compound(75 mg, 41%). Electrospray M.S. m+1=544.

Preparation 16 3-Bromo-4-methoxy-N,N-dimethylbenzenesulfonamide

Combine 3-bromo-4-methoxybenzenesulfonyl chloride (1.0 g, 3.5 mmol) anddimethylamine (8.75 ml of 1M solution in THF, 8.75 mmol) in 25 mlanhydrous THF and heat under reflux in a nitrogen atmosphere for 30minutes. Concentrate the cooled mixture in vacuo and partition theresidue between ethyl acetate and water. Wash the organic layer with 0.1N HCl solution, 0.1 N NaOH solution and brine and dry over

anhydrous sodium sulfate. Evaporate the solvent and recrystallize thecrude solid from ethyl acetate/hexane to yield the title compound (680mg, 66% yield).

Preparation 174-Methoxy-3-{6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-N,N-dimethyl-benzenesulfonamide

Dissolve 2-trifluoromethanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-napthalen-2-yl ester(590 mg, 1.10 mmol) in 15 mL acetonitrile and degas under N₂. Addbis-neopentylglycolato diborane (0.31 g, 1.38 mmol), palladium acetate(0.037 g, 0.165 mmol), and tricyclohexyl phosphine (0.069 g, 0.25 mmol),and degas again under N₂. Stir the mixture until all reagents dissolve.Add cesium fluoride (1.50 g, 9.9 mmol), and immediately place thereaction into a 90° C. preheated oil bath. After 3-7 minutes, add3-bromo-4-methoxy-N,N-dimethylbenzenesulfonamide (360 mg, 1.21 mmol) in10 mL acetonitrile and stir the mixture at 90° C. for 6 hours. Cool themixture, filter through a thin layer silica gel and the silica washedwith acetonitrile. Concentrate the filtrate in vacuo to give aquantitative crude yield of the title product, electro spray MS: 603(M+1).

EXAMPLE 82-Hydroxy-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-9-sulphonicacid dimethylamide hydrochloride salt

Slowly bubble gaseous HCl into a solution of4-methoxy-3-{6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-N,N-dimethyl-benzenesulfonamide(710 mg crude, 1.1 mmol) in DCM (15 mL). Stir the solution for 15minutes and concentrate in vacuo. Dissolve the residue in DCM (15 mL),cool to 0° C. and add boron tribromide (2.48 g, 9.9 mmol) dropwise. Stirthe reaction at 0° C. for 1.5 hours and then stir at room temperaturefor 20 minutes. Add saturated aqueous NaHCO₃ (100 ML), extract theaqueous mixture 3 times with CHCl₃/i-PrOH (4:1), dry the combinedorganic layers over Na₂SO₄ and concentrate in vacuo. Purify the residueby radial chromatography (silica, CH₂Cl₂/2M NH₃ in methanol, gradientfrom 2% to 5%) to give4-hydroxy-3-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-N,N-dimethyl-benzenesulfonamide(0.36 g, 57%). Electrospray MS: 575 (M+1).

Dissolve4-hydroxy-3-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-N,N-dimethyl-benzenesulfonamide(360 mg, 0.63 mmol) at room temperature in THF (10 mL), under N₂. Slowlyadd lithium aluminum hydride (1M solution in THF, 1.25 ml, 1.25 mmol)dropwise and stir the reaction at room temperature for 2.5 hours. Quenchthe mixture with H₂O (a few drops) until no further gas evolution andadd HCl (1N, 3 mL). After stirring the mixture at room temperature fortwo hours, remove the THF in vacuo, and add saturated aqueous NaHCO₃until the mixture is neutral to hydrion paper. Extract the aqueous phaseis 3 times with CH₂Cl₂/i-PrOH (4:1) and dry the combined organic layersover Na₂SO₄. Evaporate the solvent to yield a crude solid and purify byradial chromatography on silica eluting with a gradient of 2% to 5% 2NNH₃/MeOH in CH₂Cl₂. After evaporation of the solvent, which yields thefree base, redissolve the residue in a small amount of acetonitrile andadd five drops 1N HCl. Evaporation of solvent yields the title product(170 mg, 46% yield), electrospray MS: 559 (M+1, parent ion).

Preparation 18 3-Bromo-4-methoxy-N-methylbenzenesulfonamide

Combine 3-bromo-4-methoxybenzenesulfonyl chloride (1.0 g, 3.5 mmol) andmethylamine (4.4 ml of 2M solution in THF, 8.8 mmol) in 25 ml anhydrousTHF and heat under reflux in a nitrogen atmosphere for 30 minutes.Concentrate the cooled mixture in vacuo and partition the residuebetween ethyl acetate and water. Wash the organic layer with 0.1 N HClsolution, 0.1 N NaOH solution and brine and dry over anhydrous sodiumsulfate. Evaporate the solvent and recrystallize the crude solid fromethyl acetate/hexane to yield the title compound (340 mg, 35% yield).

Preparation 194-Methyoxy-3-{6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-N-methyl-benzenesulfonamide

Dissolve 2-trifluoromethanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-napthalen-2-yl ester(590 mg, 1.10 mmol) in 15 mL acetonitrile and degas under N₂. Addbis-neopentylglycolato diborane (0.31 g, 1.38 mmol), palladium acetate(0.037 g, 0.165 mmol), and tricyclohexyl phosphine (0.069 g, 0.25 mmol),and degas again under N₂. Stir the mixture until all reagents dissolve.Add cesium fluoride (1.50 g, 9.9 mmol), and immediately place thereaction into a 90° C. preheated oil bath. After 3-7 minutes, add3-bromo-4-methoxy-N-methylbenzenesulfonamide (340 mg, 1.21 mmol) in 10mL acetonitrile and stir the mixture 90° C. for 48 hours. Cool themixture, filter through a thin layer of silica gel and wash the silicawith acetonitrile. Concentrate the filtrate in vacuo and purify theresidue by radial chromatography (silica, CH₂Cl₂/2M NH₃ in methanol,gradient from 2% to 6%) to yield the title product, 260 mg, 41% yield.Electrospray MS: 589 (M+1).

EXAMPLE 92-Hydroxy-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-9-sulfonicacid methylamide hydrochloride salt

Slowly bubble gaseous HCl into a solution of4-methoxy-3-{6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-methyl-benzenesulfonamide(260 mg, 0.44 mmol) in DCM (5 mL). Stir the solution for 15 minutes andconcentrate in vacuo. Dissolve the residue again in DCM (5 mL), cool to0° C. and add boron tribromide (880 mg, 3.5 mmol) dropwise. Stir thereaction at 0° C. for 2 hours then stir at room temperature for 1 hour.Add saturated aqueous NaHCO₃ (100 mL) and extract the aqueous mixture 3times with CH₂Cl₂/i-PrOH (4:1). Dry the combined organic layers overNa₂SO₄ and evaporate in vacuo to give4-hydroxy-3-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-N-methyl-benzenesulfonamide(250 mg, quantitative crude yield). electrospray MS: 561 (M+1).

Dissolve4-hydroxy-3-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-N-methyl-benzenesulfonamide(250 mg, 0.44 mmol) at room temperature in THF (5 mL), under N₂. Slowlyadd lithium aluminum hydride (1M solution in THF, 0.88 ml, 0.88 mmol)dropwise and stir the reaction at room temperature for 2.5 hours. Quenchthe mixture with H₂O (a few drops) until no further gas evolution, andadd HCl (1N, 3 mL). After stirring the mixture at room temperature fortwo hours, remove the THF in vacuo, and add saturated aqueous NaHCO₃until the mixture is neutral to hydrion paper. Extract the aqueous phase3 times with CH₂Cl₂/i-PrOH (4:1) and dry the combined organic layersover Na₂SO₄. Dissolve the residue obtained after evaporation of solventin 8 ml THF and, then, add 2 ml 1N HCl. Stir the mixture at roomtemperature for three hours and warm to 45° C. for 1.5 hours.Evaporation of solvent yields a crude solid. Purify this solid by silicagel radial chromatography eluting with a gradient of 3% to 6% 2NNH₃/MeOH in CH₂Cl₂. Dissolve the free base obtained after evaporation ofsolvent in a small amount of acetonitrile and add three drops 1N HCl.Evaporation of solvent yields the title product (0.054 g, 21% yield).Electrospray MS: 545 (M+1, parent ion).

Preparation 20 2-Bromo-4-methanesulfonyl-1-methoxy-benzene

Dissolve 3-bromo-4-methoxybenzenesulfonyl chloride (2.86 g, 10 mmol) in40 ml THF at room temperature. Add 10 ml of aqueous saturated ammoniumchloride solution. While stirring, chill in an ice water bath and addzinc dust (0.72 g, 11 mmol) in small portions. Next add iodomethanedropwise over ten minutes and continue to stir the mixture in the icebath for two hours. Partition the mixture between diethyl ether andwater. Wash the organic layer with brine and dry over anhydrous sodiumsulfate. Evaporate the solvent and recrystallize the crude solid fromhexanes/diethyl ether to yield the title compound (0.34 g, 12% yield).

EXAMPLE 109-Methanesulfonyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-olhydrochloride salt

The title compound is prepared from2-bromo-4-methanesulfonyl-1-methoxy-benzene and2-trifluoromethanesulfonic acid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-napthalen-2-yl esteras described for the preparation of Examples 10 and 11. Electrospray MS:530 (M+1, parent ion).

Formulation

Because the free base form of a compound of formula I contains a basicmoiety (i.e., amino), said compound may be formulated as apharmaceutical acid addition salt, e.g., as the hydrochloride salt or asa salt described in “Handbook of Pharmaceutical Salts: Properties,Selection and Use”, Weinheim, New York: VHCA; Wiley-VCH, 2002.

The present pharmaceutical compositions are prepared by known proceduresusing well-known and readily available ingredients. In making theformulations of the present invention, the active ingredient (formula Icompound) will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a capsule,sachet, paper or other container. When the carrier serves as a diluent,it may be a solid, semisolid or liquid material which acts as a vehicle,excipient or medium for the active ingredient.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents.

Biological Assays

Estrogen Receptor Binding Assay: Representative compounds of the presentinvention are screened for binding affinity to both estrogen receptortypes (ERα and ERβ). This competition binding assay measures thecompound's ability to displace ³H-estradiol and generates IC₅₀ and K_(i)values for both receptor types.

This competition binding assay is run in a buffer containing 50 mMHepes, pH 7.5, 1.5 mM EDTA, 150 mM NaCl, 10% glycerol, 1 mg/mL ovalbuminand 5 mM DTT, using 0.025 μCi per well ³H-Estradiol(NEN #NET517 at 118Ci/mmol, 1 mCi/mL), 10 ng/well ERAlpha or ERbeta receptor (PanVera). Acompound of the present invention is added at 10 differentconcentrations. Non-specific binding is determined in the presence of 1μM of 17-B Estradiol. The binding reaction (140 μL) is incubated for 4hours at room temperature, then 70 μl of cold DCC buffer is added toeach reaction (DCC buffer contains per 50 mL of assay buffer, 750 mg ofcharcoal (Sigma) and 250 mg of dextran (Pharmacia)). Plates are mixed 8minutes on an orbital shaker at 4° C. Plates are then centrifuged at3,000 rpm at 4° C. for 10 minutes. An aliquot of 120 μl of the mix istransferred to another 96-well, white flat bottom plate (Costar) and 175μl of Wallac Optiphase “Hisafe 3” scintillation fluid is added to eachwell. Plates are sealed and shaken vigorously on an orbital shaker.After an incubation of 2.5 hours, the plates are read in a WallacMicrobeta counter. The data is used to calculate an IC₅₀ and %Inhibition at 10 μM. The K_(d) for ³H-Estradiol is determined bysaturation binding to ER alpha and ER beta receptors. The IC₅₀ valuesfor test compounds are converted to K_(i) using Cheng-Prusoff equationand the K_(d) determined by saturation binding assay.

Ishikawa Cell Proliferation Assay: This assay measures cellproliferation (using an alkaline phosphatase readout) in both an agonistmode in the presence of a compound of the present invention alone, andin an antagonist mode in which the ability of a compound of the presentinvention to block estradiol stimulation of growth is measured.

Ishikawa human endometrial tumor cells are maintained in MEM (minimumessential medium, with Earle's salts and L-Glutamine, Gibco BRL,Gaithersburg, Md.), supplemented with 10% fetal bovine serum (FBS)(V/V), (Gibco BRL). One day prior to assay, growth media is changed toassay medium, DMEM/F-12 (3:1) (Dulbecco's Modified Eagle Medium:Nutrient Mixture F-12, 3:1 Mixture, phenol red-free, Gibco BRL)supplemented with 5% dextran coated charcoal stripped fetal bovine serum(DCC-FBS) (Hyclone, Logen, Utah), L-Glutamine (2 mM), MEM sodiumpyruvate (1 mM), HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid] 2 mM) all fromGibco BRL). After an overnight incubation, Ishikawa cells are rinsedwith Dulbecco's Phosphate Buffered Saline (1×) (D-PBS) without Ca⁺² andMg⁺² (Gibco BRL), and trypsinized by a 3 minute incubation with 0.25%Trypsin/EDTA, phenol red-free (Gibco BRL). Cells are resuspended inassay medium and adjusted to 250,000 cells/mL. Approximately 25,000cells in a 100 μl media are added to flat-bottom 96 wells microcultureplates (Costar 3596) and incubated at 37° C. in a 5% CO₂ humidifiedincubator for 24 hours. The next day, serial dilutions of compounds areprepared in assay medium (at 6 times the final concentration in theassay). The assay is run in dual mode, agonist and antagonist modes.

For the agonist mode, plates receive 25 μl/well of assay medium followedby 25 μl/well of a diluted compound of the present invention (at 6× thefinal concentrations). For the antagonist mode, plates receive 25μl/well of 6 nM E₂ (β-Estradiol, Sigma, St. Louis, Mo.) followed by 25μl/well of a diluted compound of the present invention (at 6× the finalconcentrations). After an additional 48-hour incubation at 37° C. in a5% CO₂ humidified incubator, media is aspirated from wells and 100 μlfresh assay medium is added to each microculture. Serial dilutions ofcompounds are prepared and added to the cells as described above. Afteran additional 72 hour incubation at 37° C. in a 5% CO₂ humidifiedincubator, the assay is quenched by removing media and rinsing platestwice in Dulbecco's Phosphate Buffered Saline (1×) (D-PBS) (Gibco BRL).The plates are dried for 5 minutes and frozen at −70° C. for at least 1hour. The plates are then removed from the freezer and allowed to thawat room temperature. To each well, 100 μl of 1-Step™ PNPP (PierceChemical Company, Rockford, Ill.) is added. After a 20-minuteincubation, plates are read on a spectophotometer at 405 nm.

The data is fitted to a linear interpolation to derive EC₅₀ (for agonistmode) or IC₅₀ (for antagonist mode) values. For the antagonist mode, a %efficacy for each compound is calculated versus E2 (1 nM) alone. For theagonist mode, a % efficacy for each compound is calculated versus theresponse to tamoxifen.

In the agonist mode, the compounds of Examples 1, 3, 5, 7, 9, 10 and 11were tested and were found to be less stimulatory than tamoxifen. Forexample, the compound of Example 1 had a relative % efficacy of 26%. Inthe antagonist mode, this same compound inhibited greater than at least65% of the 1 nM estradiol response. For example, the compound of Example1 had an IC₅₀ of 45 nM and a % efficacy of 92%.

MCF-7 Proliferation Assay: The MCF-7 cell line is derived from a humanbreast adenocarcinoma and is used as an indicator of potentialantiproliferative activity in breast epithelium.

MCF-7 breast adenocarcinoma cells (ATCC HTB 22) are maintained in MEM(minimal essential medium, phenol red-free, Gibco BRL) supplemented with10% fetal bovine serum (FBS) (V/V), L-glutamine (2 mM), sodium pyruvate(1 mM), HEPES ((N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonicacid]10 mM}, non-essential amino acids (0.1 mM) and PenicillinStreptomycin (1×). Seven days prior to assay, MCF-7 cells are switchedto assay media which is the same as maintenance medium exceptsupplemented with 10% dextran-coated charcoal-stripped fetal bovineserum (DCC-FBS) assay medium in place of 10% FBS. MCF-7 cells areremoved from flasks using 10×Trypsin EDTA (phenol red free, Gibco BRL)and diluted to 1× in (Ca++/Mg++ free HBSS (phenol red-free). Cells areadjusted to 80,000 cells/mL in assay medium. Approximately 8,000 cells(100 μl) are added to each well in 96 well Cytostar T scintillationplates (Amersham) and incubated at 37° C. in a 5% CO₂ humidifiedincubator for 24 hours to allow cell adherence and equilibration aftertransfer.

Serial dilutions of a compound of the present invention are prepared inassay medium at 4× the final desired concentration). A 50 μl aliquot oftest compound dilutions (at 4× the final assay concentration) istransferred to duplicate wells followed by 50 μl assay medium for theagonist mode or 50 μl of 40 pM of E2 for the antagonist mode to a finalvolume of 200 μl. For each of the agonist plates, a basal level (media)and a maximum stimulated level (with 1 μM E2) is determined. For each ofthe antagonist plates, a basal level (media) and an E2 (10 pM) alonecontrol is determined. After an additional 48 hours at 37° C. in a 5%CO₂ humidified incubator, 20 μl of assay medium containing 0.01 μCi of¹⁴C-thymidine (52 mCi/mmol, 50 μCi/ul, Amersham) is added to each well.The plates are incubated overnight in the same incubator and thencounted on the Wallac Microbeta counter. The data is averaged tocalculate an IC₅₀ and % inhibition@1 μM for the antagonist mode. For theagonist mode, an EC₅₀ and percent of maximum E2 stimulation andconcentration of maximum stimulation is calculated.

3-Day Rat Uterus Antagonist Assay: This model for uterine antagonismutilizes immature (3 week old) female rats that are highly sensitive toestrogenic stimulation of the uterus given that their circulatingestrogen levels are prepubertal. The uteri from immature rats are fullyresponsive to exogenous estrogen, yet are quiescent in the absence ofexogenous estrogen. Administration of exogenous estrogen to immaturerats produces a reliable elevation of uterine weight, which can be usedto study uterine antagonist effects. The rats are treated with bothestradiol and 4 different concentrations of a compound of the presentinvention for 3 days and then uterine wet weights are measured.

Nineteen to twenty-one day old (or 45-50 g) female rats are orallytreated with E2 (0.1 mg/kg, a maximal stimulatory estrogenic stimulusfor reliably increasing uterine weight) and 10, 1.0, 0.1 and 0.01 mg/kgtest compound for 3 days, 6 rats per group. Test compounds are dissolvedin 20% β-hydroxycyclodextrin and administered by oral gavage in a volumeof 0.2 mL daily (15 min. prior to the ethynyl estradiol gavage). Avehicle control, E2 alone and E2+raloxifene are also done as controls.The animals are fasted overnight following the final dose. On thefollowing morning, the animals are weighed, then euthanized (by carbondioxide asphyxiation) and the uteri rapidly collected (via a mid-lineventral incision) and weighed.

Uterine weight/body weight ratios (UWR) are calculated for each animal.The percent inhibition of the estrogen-induced response is thencalculated by the following formula: percentinhibition=100×(UWR_(estrogen)−UWR_(test compound)/UWR_(estrogen)−UWR_(control)).ED₅₀ values are derived from a semi-log regression analysis of thelinear aspect of the dose response curve. Both the UWR data and thepercent inhibition data are statistically analyzed by one way analysisof variance (ANOVA) with post-hoc testing by Fisher's PLSD whenindicated by a p≦0.05. Statistical analyses are performed using theStatview® 4.0 software package.

The compounds of Examples 1 and 3 were tested in the above assay andwere found to inhibit the estrogen-induced response when administered at0.01, 0.1 and 1.0 mg/kg. For example, the compounds of Examples 1 and 3had an ED₅₀ of 0.22 and 0.17 mpk and a % antagonism of 69 and 81%,respectively.

4-Day OVX Rat Uterine Agonist Assay: In order to assure that a testcompound does not have any partial uterine agonist activity, compoundsare administered to mature, ovariectomized rats.

Seventy-five day old rats are ovariectomized and treatment is started 14days later when circulating estradiol levels have reached minimallevels. After 4 days of treatment with 3 doses of a compound of thepresent invention, (6 rats per group) body weight, uterine wet weightand uterine eosinophil peroxidase (EPO) activity are measured.Cholesterol levels are also measured to compare relative ability tolower cholesterol with other SERMs. If there is any question of uterinestimulation, histological examination will determine epithelial cellheight.

10-Day Rat Hormone (Ovarian Stimulation) Screen: An initial, firstscreen for ovarian toxicity is conducted using a 10-day rat hormonestudy to measure estradiol and luteinizing hormone levels after compoundadministration. This screen is conducted by administering compound byoral gavage for 10 days to mature (9-10 week old) F344 female rats.Trunk blood is collected by rapid decapitation for evaluation of LH andestradiol levels approximately 2 hours after the 10^(th) dose. Serum,obtained by centrifugation, is removed and stored frozen below −60° C.until assayed. Serum levels of LH and estradiol are measured usingradioimmunoassay (RIA) methods.

Rat LH primary antibody and reference preparations (rat LH:RP-3) areobtained from Dr. A. F. Parlow, Director, Pituitary Hormones andAntisera Center, Harbor-UCLA Medical Center, Torrance, Calif. The LHassay upper limits of detection are 30 ng/mL and the lower limits ofdetection are 0.1 ng/mL for the 100 μl samples.

E2 Clinical Assays. DiaSorin s.r.l., Saluggia (Vercelli), Italy. Theupper limit of detection is 1000 pg/mL and the lower limit of detectionis 5 pg/mL. The compound of Example 3 was tested in the above assay anddid not significantly elevate circulating estradiol or LH levels.

35-Day Ovary-Intact Rat Bone Assay: While previous SERMs, includingraloxifene have shown efficacy in preventing bone loss in OVX rats, thepossibility of interference with estrogen-regulated turnover inovary-intact rats needs to be addressed.

This assay is done in mature rats with concentrations based on thedemonstrated efficacy in the 3-day assay. Generally, at least threeconcentrations are chosen based on multiples of the ED₅₀ generatedtherein. These multiples are generally 1×, 10× and 30× the ED₅₀. Acompound of the present invention is administered to an OVX rat for 35days and is compared to control, ovariectomized, and/orGnRH-administered rats. Femurs, tibiae, uteri, ovaries and serum aretaken for further analyses. DEXA (Dual Energy X-ray Absorptivity), CT(Computed Tomography) and histologic analysis are done on the long bonesto assess any changes. CT scans of the distal femur are done tocalculate BMD (bone mineral density), cross sectional area and BMC (bonemineral content). Bone strength measurements (load to failure) may alsobe done to determine consequences of any bone mass or material changes.Uterine and ovarian histology are examined to confirm long term dosingeffects of uterine efficacy and potential ovarian stimulation. The serumis analyzed for LH and E2 levels as a possible indicator of ovarianeffects.

Utilities

The diseases, disorders or conditions for which a compound of formula Iis useful in treating include, but are not limited to, (1) uterinecancer; (2) endometriosis; (3) uterine leiomyoma/leiomyomata; (4)post-menopausal osteoporosis, i.e., osteoporosis caused by the loss ofbone that results from a lack of endogenous estrogen such as occurs in awoman following cessation of menstration due to natural, surgical, orother processes; and (5) estrogen receptor positive (ER+) breast cancer,particularly the prevention thereof. Treatment of uterineleiomyoma/leiomyomata as described herein, also contemplates thereduction of the occurrence or severity of the associated symptoms suchas pain, urinary frequency, and uterine bleeding.

Dose

The specific dose administered is determined by the particularcircumstances surrounding each situation. These circumstances include,the route of administration, the prior medical history of the recipient,the pathological condition or symptom being treated, the severity of thecondition/symptom being treated, and the age of the recipient. Therecipient patient's physician should determine the therapeutic doseadministered in light of the relevant circumstances.

Generally, an effective minimum daily dose of a compound of formula Iwill exceed about 5 mg. Typically, an effective maximum daily dose willnot exceed about 350 mg. The exact dose may be determined, in accordancewith the standard practice in the medical arts of “dose titrating” therecipient; that is, initially administering a low dose of the compound,and gradually increasing the does until the desired therapeutic effectis observed.

1. A compound of formula I:

wherein: m and r are independently 0, 1 or 2; R is H, SO₂(n-C₄-C₆ alkyl)or COR³; R⁰ is independently at each occurrence OH, CF₃, halo, C₁-C₆alkyl or C₁-C₆ alkoxy; R¹ is C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁴R^(4a), CF₃or CH₂CF₃; R² is H or methyl provided that if m is 1 or 2, then R² mustbe H and that if m is 0, then R² must be methyl; R³ is C₁-C₆ alkyl,C₁-C₆ alkoxy, NR⁶R^(6a), phenoxy, or phenyl optionally substituted withhalo; R⁴ is C₁-C₆ alkyl or phenyl; R^(4a), R⁶ and R^(6a) areindependently at each occurrence H, C₁-C₆ alkyl or phenyl; X is O orNR⁷; Y is O or S; and R⁷ is H or C₁-C₆ alkyl; or a pharmaceutical acidaddition salt thereof.
 2. The compound of claim 1 wherein X and Y are Oand m is 1 or
 2. 3. The compound of claim 2 wherein r is
 0. 4. Thecompound of claim 3 wherein R is H or COR³ and R³ is C₁-C₄ alkyl, NHCH₃or phenyl.
 5. The compound of claim 4 wherein R is H and m is
 1. 6. Thecompound of claim 5 wherein the SO₂R¹ moiety is at the 4-position. 7.The compound of claim 6 wherein R¹ is C₁-C₄ alkyl, CF₃ or NR⁴R^(4a) andR⁴ is C₁-C₄ alkyl and R^(4a) is H or C₁-C₄ alkyl.
 8. The compound ofclaim 7 wherein R¹ is methyl, ethyl, cyclopropyl, CF₃, NHCH₃ or N(CH₃)₂.9. The compound of claim 1 selected from the group consisting of:

or a pharmaceutical acid addition salt thereof.
 10. (canceled) 11.(canceled)
 12. A method of treating uterine leiomyoma comprisingadministering to a patient in need thereof an effective amount of acompound of claim
 1. 13. (canceled)
 14. A compound of formula II:

wherein: m and r are independently 0, 1 or 2; q is 0 or 1; s is 0, 1 or2; R⁰ is independently at each occurrence OH, CF₃, halo, C₁-C₆ alkyl orC₁-C₆ alkoxy; R¹ is C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁴R^(4a), CF₃ or CH₂CF₃;R² is H or methyl provided that if m is 1 or 2, then R² must be H andthat if m is 0, then R² must be methyl; R⁸ is H, C₁-C₆ alkyl, benzyl,SO₂CH₃, SO₂(n-C₄-C₆ alkyl) or COR³; R³ is C₁-C₆ alkyl, C₁-C₆ alkoxy,NR⁶R⁶a, phenoxy, or phenyl optionally substituted with halo; R⁴ is C₁-C₆alkyl or phenyl; R^(4a), R⁶ and R^(6a) are independently at eachoccurrence H, C₁-C₆ alkyl or phenyl; X¹ is O or NR⁹; Y is O or S; and R⁹is H, C₁-C₆ alkyl or CO₂(C₁-C₆ alkyl); provided that if s is 2, then R⁸is C₁-C₆ alkyl, SO₂CH₃ or benzyl or R⁹ is CO₂(C₁-C₆ alkyl); or an acidaddition salt thereof.
 15. The compound of claim 14 wherein X¹ and Y areO and m is 1 or
 2. 16. The compound of claim 15 wherein r is
 0. 17. Thecompound of claim 16 wherein R⁸ is SO₂CH₃, benzyl or methyl.
 18. Thecompound of claim 17 wherein m is
 1. 19. The compound of claim 18wherein the SO_(S)R¹ moiety is at the 4-position.
 20. The compound ofclaim 19 wherein R¹ is C₁-C₄ alkyl, CF₃ or NR⁴R^(4a) and R⁴ is C₁-C₄alkyl and R^(4a) is H or C₁-C₄ alkyl.
 21. The compound of claim 20wherein R¹ is methyl, ethyl, cyclopropyl, CF₃, NHCH₃ or N(CH₃)₂.